The present invention relates to a novel process for the preparation of 3-alkoxymethylcephalosporin derivatives from the corresponding 3-acetoxymethylcephalosporin derivatives.
Although many cephalosporin derivatives have been developed in recent years, often the practical, therapeutic use of these derivatives is delayed or prevented by problems with their production, and this may apply even where the derivatives are recognised to have valuable therapeutic activity.
The majority of cephalosporin derivatives elaborated by microorganisms possess an acetoxymethyl group at the 3-position. In the course or preparing therapeutically useful cephalosporin derivatives, it is often necessary to convert this acetoxymethyl group to other groups (generally substituted methyl groups), for example to alkoxymethyl groups. The following methods of preparing 3-alkoxymethylcephalosporin derivatives from the corresponding 3-acetoxymethylcephalosporin derivatives are known:
(A) The reaction of a 3-acetoxymethylcephalosporin derivative with a lower alkanol is described in U.S. Pat. No. 3,665,003. This process has the advantage of directly producing the desired 3-alkoxymethylcephalosporin derivative from the corresponding acetoxymethyl compound in a single step, but the yields obtained are very low and isolation and purification of the final product are difficult.
(B) Also described in said U.S. Pat. No. 3,665,003 is the preparation of 3-alkoxymethylcephalosporin derivatives by alkylating the corresponding 3-hydroxymethyl compound using a diazoalkane. This method also gives rise to some difficulties, in that the 3-acetoxymethyl group must first be converted to a 3-hydroxymethyl group, that the carboxy group at the 4-position must be protected and that diazoalkanes are toxic and dangerous to use; accordingly, it is undesirable to use large quantities of diazoalkanes, for example diazomethane. However, the yield from the alkylation step when using diazomethane in the presence of boron trifluoride is high. More conventional alkylating agents, such as methyl iodide, cannot be used, since these necessitate the conversion of the 3-hydroxymethyl group to a 3-sodiooxymethyl group and this conversion reaction inevitably gives rise to some damage to the .beta.-lactam ring.
(C) U.S. Pat. No. 3,658,799 discloses the reaction of a 3-halomethyl compound with a lower alkanol to give the desired 3-alkoxymethylcephalosporin derivative. This reaction, however, requires three steps, including protection of the carboxy group at the 4-position, and the yields obtained in the reaction of the 3-halomethyl compound with the alkanol are not always good.
(D) U.S. Pat. No. 3,658,799 also discloses the reaction of a 3-haloacetoxymethylcephalosporin derivative with a lower alkanol. However, the preparation of the 3-haloacetoxymethyl compound used as starting material in this process from the original 3-acetoxymethyl compound requires three or four steps and, again, the yields obtained in the reaction with the alkanol are not good.
(E) 3-Alkoxymethylcelphalosporin derivatives can also be prepared by reacting a 3-halomethyl-2-cephem compound, with a lower alkanol to give a 3-alkoxymethyl-2-cephem compound, which is then isomerized to the desired 3-alkoxymethyl-3-cephem comound, as described in J. Med. Chem. 14,113 (1971). This method, however, requires many steps, as a 3-cephem compound, which is the compound originally obtained by fermentation, has first to be isomerized to the 2-cephem compound; the 3-methyl group of this compound has to be selectively halogenated; the compound is then reacted with the lower alkanol; and finally the 2-cephem compound has to be isomerized again to restore the 3-cephem compound; in addition, various of the substituent groups of the cephalosporin derivatives may need to be protected during one or more of these reactions.
In general, it is desirable to avoid multi-stage reactions, since the use of many reagents tends to make them expensive and since overall yields are generally rather low, as each additional reaction stage (unless the reaction takes place quantitatively, which is rare) leads to a reduction in overall yields.
For these reasons, although many cephalosporin derivatives having an alkoxymethyl group at the 3-position have been found to be valuable antibiotics, for example as described in U.S. patent application Ser. No. 304,988, filed Sept. 23, 1981, it is difficult to put them to practical use.
We have now discovered a method of converting the 3-acetoxymethyl group of 3-acetoxymethylcephalosporin derivatives to a 3-alkoxymethyl group in a single step and in relatively good yields.
The cephalosporin derivatives to which the process of the present invention is applied are compounds having a basic skeletal structure which may be represented as follows: T,0060
Such compounds have a carboxy group (or various derivatives of the carboxy group) at the 4-position. Compounds having a carboxy group at the 4-position are known as cephalosporanic acids or 3-cephem-4-carboxylic acids and are referred to as such herein. The compounds normally also have an amino group (or substituted amino group) and a hydrogen atom at the 7-position, although compounds having an alkoxy (generally methoxy) group at the 7-position and an amino or substituted amino group at the 7.beta.-position are known.